Ischemic preconditioning has been shown to protect against ischemic damage when given prior to a lethal ischemia, however, its clinical application for stroke patients is possible only when stroke occurrence is predictable. Post-stroke strategies are more feasible for treating patients. One potential post-stroke target is to reduce the damage caused by reperfusion after ischemia. Altering reperfusion in myocardial ischemia has been shown to reduce infract size. Two methods were employed to alter reperfusion: a controlled restoration of blood flow to give a gradual reperfusion;or postconditioning, where reperfusion is interrupted several times. This concept of altered reperfusion has not been tested in the field of stroke research. Thus, we propose to study whether postconditioning or gradual reperfusion reduces ischemic damage after stroke. In our pilot study we found that one model of postconditioning reduced damage in a model of focal ischemia generated by transient bilateral common carotid artery (CCA) occlusion combined with middle cerebral artery (MCA) occlusion. Postconditioning was achieved by a series of short interruptions during reperfusion by releasing and re-occluding the CCAs. We propose to further define the temporal characteristics for postconditioning using this model. In addition, since we previous found that partial reperfusion reduced infarct size compared with complete reperfusion, we will further determine if gradual reperfusion also reduces ischemic damage using a similar focal ischemia model. Finally, we propose to study the potential neuroprotective mechanisms of postconditioning after stroke. In myocardial ischemia, postconditioning was found to be protective by reducing products of reactive oxygen species (ROS) and improving Akt activity. Since both of these also influence neuronal death after stroke and reperfusion, we propose to study the effect of postconditioning on ROS generation and on signals of the Akt survival pathways after stroke. Specific Aim 1. To further define temporal characteristics for postconditioning and explore if gradual reperfusion reduces ischemic infarct. Specific Aim 2. To determine if postconditioning or gradual reperfusion spare neurological function after focal ischemia in rats. Specific Aim 3. To explore the potential neuroprotective mechanisms of postconditioning focusing on Reactive Oxygen Species (ROS) generation and Akt pathway activity. PUBLIC HEALTH RELEVANCE: Postconditioning after stroke reduces ischemic damage, opening up a new avenue for research for stroke treatment. Postconditioning may eventually be clinically applicable for stroke patients.